Head and neck squamous cell carcinoma (HNSCC) is an aggressive neoplasm that is the sixth most common malignancy in the world. Despite numerous advances in treatment, the five-year survival has remained unchanged for the last 50 years. This poor outcome is due to a number of variables including delayed diagnosis as well as the development of multiple primary tumors. Therefore, it is essential to supplement early detection with effective strategies for the prevention of this devastating disease. The expression of the angiogenic phenotype is both a very early and an absolutely essential step in the development of HNSCC, making it an attractive target for cancer prevention. However, a number of critical biologic questions remain regarding the timing, mechanisms and dynamics of the angiogenic phenotype during progression. In addition, a detailed and systematic evaluation of the utility of anti-angiogenic therapies targeting the prevention of HNSCC has not been performed. The long-term goal of this proposal is to develop novel, nontoxic chemopreventive strategies for HNSCC that are based upon the inhibition of angiogenesis. The hypothesis of this work is that inhibitors of angiogenesis can effectively prevent HNSCC. The specific aims are: 1.) to characterize the development of the "angiogenic switch" in HNSCC, 2) to investigate the mechanisms and dynamics of the angiogenic phenotype during the development of HNSCC, and 3) to determine if anti-angiogenic agents ZD6474 or ABT-510 are effective as chemopreventive therapies in a pre-clinical animal model of HNSCC. Using preclinical animal models as well as human tissue/cells, the proposed work will determine the timing of the switch of the angiogenic phenotype in HNSCC. It will also investigate the mechanisms and dynamics of this switch. Finally, it will determine if inhibitors of angiogenesis are an effective treatment modality for the prevention of HNSCC, which would be of dramatic clinical benefit to large numbers of patients who are at tremendous risk for developing multiple lesions throughout their upper aerodigestive tract.